NF-kappaB includes a family of signal-activated transcription factors that normally regulate responses to injury and infection but which are aberrantly activated in many carcinomas. Cumulative evidence implicates NF-kappaB in cell survival, inflammation, angiogenesis, spread and therapeutic resistance during tumor development, progression and metastasis of carcinomas. Non-specific natural and synthetic agents that inhibit NF-kappaB have demonstrated activity and safety in prevention or therapy. NF-kappaB-activating kinases and the proteasome are under investigation for targeted prevention and therapy of carcinoma. In a phase I clinical trial of proteasome inhibitor bortezomib with reirradiation for patients with recurrent HNSCC (01-C-0104), correlative studies revealed that treatment significantly enhanced apoptosis with inhibition of nuclear RELA, but other NF-kappaB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was often observed within 3 months (Allen, Clinical Cancer Res, 2008). Studies in HNSCC cell lines, indicated that bortezomib partially inhibits basal activation of NF-kappaB1/RELA, but not NF-kappaB2/RELB, or MAPK-AP-1 activation. We conclude that although bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-kappaB or MAPK-AP-1 or STAT3 prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC. A collaborative trial (NIH protocol 08-C-0071) with NCI and University of Pittsburgh NCI SPORE investigators combining bortezomib to inhibit NF-kB, with Epidermal Growth Factor Receptor inhibitor antibody cetuximab to inhibit MAPK and STAT3, was completed (Argiris et al., Clin Cancer Res, 2011). A modest complete response rate in 3/7 subjects, with shorter than expected disease free survival, prompted closure of accrual. Correlative stuides revealed that Bortezomib antagonized degradation of Epidermal Growth Factor Receptor and ERK signaling. In the past year we completed studies that help define a role for both IKKalpha and beta in canonical and alternative NF-kB subunit activation, and EGFR-AP-1 signaling, that explain why inhibition of canonical signaling and RELA by bortezomib was insufficient, and point to potential of heat shock protein 90 inhibitors that block both pathways for therapy (Nottingham, Oncogene, 2013). As part of The Cancer Genome Atlas group characterizing head and neck cancer, we have identified components of PI3K and TNF pathway as candidate genetic drivers for aberrant NF-kB activation and defects in death signaling.